-
Frontiers in Immunology 2024Chimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid...
INTRODUCTION
Chimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid tumors.
METHODS
In this study, we created CD276-targeted CAR-expressing NK cells from pluripotent stem cells (iPSC CD276-targeted CAR-NK cells) and evaluated their cytotoxicity against esophageal squamous cell carcinoma (ESCC) using patient-specific organoid (PSO) models comprising of both CD276-positive and CD276-negative adjacent epithelium PSO models (normal control PSO, NC PSO) as well as primary culture of ESCC cell models. In addition, and models such as KYSE-150 were also examined. iPSC NK cells and NK-free media were used as the CAR-free and NK-free controls, respectively.
RESULTS
The positive CD276 staining was specifically detected on the ESCC membrane in 51.43% (54/105) of the patients of all stages, and in 51.35% (38/74) of stages III and IV. The iPS CD276-targeted CAR-NK cells, comparing with the iPS NK cells and the NK-free medium, exhibited specific and significant cytotoxic activity against CD276-positive ESCC PSO rather than CD276-negative NC PSO, and exhibited significant cytotoxicity against CD276-expressing cultured ESCC cells, as well as against CD276-expressing KYSE-150 and in BNDG mouse xenograft.
DISCUSSION
The efficacy of the iPSC CD276-targeted CAR-NK cells demonstrated by their successful treatment of CD276-expressing ESCC in a multitude of pre-clinical models implied that they hold tremendous therapeutic potential for treating patients with CD276-expressing ESCC.
Topics: Humans; Animals; Mice; Receptors, Chimeric Antigen; Induced Pluripotent Stem Cells; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; Killer Cells, Natural; B7 Antigens
PubMed: 38566988
DOI: 10.3389/fimmu.2024.1337489 -
Journal of the West African College of... 2024Fibroepithelial polyps of the Vagina (FEPV) are mucosal polypoid lesions with a connective tissue core covered by a benign squamous epithelium. They are thought to be...
Fibroepithelial polyps of the Vagina (FEPV) are mucosal polypoid lesions with a connective tissue core covered by a benign squamous epithelium. They are thought to be rare as only a few cases are reported in the literature. Fibroepithelial stromal polyps are mesenchymal neoplasms that can occur in the vagina, vulva, and even on the cervix. These fibroepithelial stromal polyps have also been reported in rare sites such as breast and labia.
PubMed: 38562389
DOI: 10.4103/jwas.jwas_121_23 -
[Clinicopathological characteristics and immune microenvironment of breast squamous cell carcinoma].Zhonghua Bing Li Xue Za Zhi = Chinese... Apr 2024To investigate the clinicopathological characteristics of breast squamous cell carcinoma and to analyze the relationship between its immune microenvironment tumor...
To investigate the clinicopathological characteristics of breast squamous cell carcinoma and to analyze the relationship between its immune microenvironment tumor infiltrating lymphocytes (TILs) and prognosis. Forty-four cases of primary squamous cell carcinoma of the breast diagnosed and treated in the First Affiliated Hospital of Air Force Medical University, Xi'an, China from January 2006 to July 2022 were selected. Their clinicopathological characteristics were analyzed. The cell composition of TILs was evaluated using immunohistochemistry (Mainly markers of B lymphocytes, T lymphocytes and plasma cells). The relationship between TILs and prognosis was also analyzed. The 44 patients of breast squamous cell carcinoma were all female and all were invasive carcinoma. Eight cases (8/44, 18.2%) were squamous cell carcinoma, while 36 cases (36/44, 81.8%) were mixed squamous cell carcinoma. The mixed components included non-specific carcinoma and spindle cell metaplastic carcinoma (17 cases each). One case contained ductal carcinoma in situ of the breast and 1 case contained tubular carcinoma. The proportion of squamous cell carcinoma was 10% to 90%. The cases with pure squamous cell carcinoma often had a large cystic cavity, which was lined by atypical squamous epithelium, while infiltrating squamous cell carcinoma nests were seen in the breast tissue around the cystic cavity. Immunohistochemical staining showed that p63 and CK5/6 were expressed in the squamous cell carcinoma component, but ER, PR and HER2 were not, except for one case of HER2 1+. The positive rates of TRPS1 and PDL-1 were 76% and less than 1%, respectively. Fifteen cases were in the high TILs group (TILs≥30%) and 29 cases were in the low TILs group (TILs<30%). Twenty-three patients were followed up for 5 to 118 months. Among them, 12 died within 3 years and 9 were alive at the end of the follow up. There was no significant difference in TNM stage, TILs and prognosis between simple squamous cell carcinoma and mixed squamous cell carcinoma. Breast squamous cell carcinoma can be divided into simple squamous cell carcinoma and mixed squamous cell carcinoma. There are differences in gross findings and histology between the simple and mixed squamous cell carcinoma of the breast. Sufficient samples should be taken to avoid missing the diagnosis of a minor squamous component. The prognosis of patients with high TILs is significantly better than that of patients with low TILs. The expression rate of TRPS1 in primary squamous cell carcinoma of breast is high and helpful to the differential diagnosis from metastatic squamous cell carcinoma.
Topics: Humans; Female; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Squamous Cell; Prognosis; Lymphocytes, Tumor-Infiltrating; Tumor Microenvironment; Repressor Proteins
PubMed: 38556816
DOI: 10.3760/cma.j.cn112151-20231023-00293 -
Biology Mar 2024Transient receptor potential vanilloid-6 (TRPV6) is a cation channel belonging to the TRP superfamily, specifically the vanilloid subfamily, and is the sixth member of... (Review)
Review
Transient receptor potential vanilloid-6 (TRPV6) is a cation channel belonging to the TRP superfamily, specifically the vanilloid subfamily, and is the sixth member of this subfamily. Its presence in the body is primarily limited to the skin, ovaries, kidney, testes, and digestive tract epithelium. The body maintains calcium homeostasis using the TRPV6 channel, which has a greater calcium selectivity than the other TRP channels. Several pieces of evidence suggest that it is upregulated in the advanced stages of thyroid, ovarian, breast, colon, and prostate cancers. The function of TRPV6 in regulating calcium signaling in cancer will be covered in this review, along with its potential applications as a cancer treatment target.
PubMed: 38534438
DOI: 10.3390/biology13030168 -
Scientific Reports Mar 2024Biophysical cues from the cell microenvironment are detected by mechanosensitive components at the cell surface. Such machineries convert physical information into...
Biophysical cues from the cell microenvironment are detected by mechanosensitive components at the cell surface. Such machineries convert physical information into biochemical signaling cascades within cells, subsequently leading to various cellular responses in a stimulus-dependent manner. At the surface of extracellular environment and cell cytoplasm exist several ion channel families that are activated by mechanical signals to direct intracellular events. One of such channel is formed by transient receptor potential cation channel subfamily V member, TRPV4 that is known to act as a mechanosensor in wide variaty of tissues and control ion-influx in a spatio-temporal way. Here we report that TRPV4 is prominently expressed in the stem/progenitor cell populations of the mammary epithelium and seems important for the lineage-specific differentiation, consequently affecting mechanical features of the mature mammary epithelium. This was evident by the lack of several markers for mature myoepithelial and luminal epithelial cells in TRPV4-depleted cell lines. Interestingly, TRPV4 expression is controlled in a tension-dependent manner and it also impacts differentation process dependently on the stiffness of the microenvironment. Furthermore, such cells in a 3D compartment were disabled to maintain normal mammosphere structures and displayed abnormal lumen formation, size of the structures and disrupted cellular junctions. Mechanosensitive TRPV4 channel therefore act as critical player in the homeostasis of normal mammary epithelium through sensing the physical environment and guiding accordingly differentiation and structural organization of the bilayered mammary epithelium.
Topics: Humans; TRPV Cation Channels; Epithelium; Signal Transduction; Epithelial Cells; Cytoplasm
PubMed: 38514727
DOI: 10.1038/s41598-024-57346-x -
International Journal of Molecular... Feb 2024Pigment epithelium-derived factor (PEDF), a serine protease inhibitor (Serpin) family member, shows promise in inhibiting tumour growth. In our study, we explored the...
Pigment epithelium-derived factor (PEDF), a serine protease inhibitor (Serpin) family member, shows promise in inhibiting tumour growth. In our study, we explored the effects of PEDF on the efficacy of the frontline chemotherapy agent doxorubicin (Dox) in BC cells. We found that Dox+PEDF treatment significantly reduced glucose uptake in MDA-MB-231 cells compared to the control ( = 0.0005), PEDF ( = 0.0137), and Dox ( = 0.0171) alone but paradoxically increased it in MCF-7 cells. Our findings further revealed that PEDF, Dox, and Dox+PEDF substantially hindered tumour cell migration from tumour spheroids, with Dox+PEDF showing the most significant impact ( < 0.0001). We also observed notable decreases in the expression of metastatic markers (uPAR, uPA, CXCR4, MT1-MMP, TNF-α) across all treatment groups ( < 0.0001) in both cell lines. When it comes to metabolic pathways, PEDF increased phosphorylated IRS-1 (p-IRS1) levels in MDA-MB-231 and MCF-7 ( < 0.0001), while Dox decreased it, and the combination led to an increase. In MDA-MB-231 cells, treatment with PEDF, Dox, and the combination led to a notable decrease in both phosphorylated AKT (p-AKT) and total AKT levels. In MCF-7, while PEDF, Dox, and their combination led to a reduction in p-AKT, total levels of AKT increased in the presence of Dox and Dox+PEDF. Combining PEDF with Dox enhances the targeting of metastatic and metabolic pathways in breast cancer cell lines. This synergy, marked by PEDF's increasing roles in cancer control, may pave the way for more effective cancer treatments.
Topics: Humans; Female; Serpins; Proto-Oncogene Proteins c-akt; Breast Neoplasms; Doxorubicin; MCF-7 Cells; Cell Line, Tumor; Apoptosis; Eye Proteins; Nerve Growth Factors
PubMed: 38474001
DOI: 10.3390/ijms25052755 -
Cancers Feb 2024Obesity is strongly associated with occurrence, metastasis, and resistance to therapy in breast cancers, which also exhibit high adipose content in the tumor...
Obesity is strongly associated with occurrence, metastasis, and resistance to therapy in breast cancers, which also exhibit high adipose content in the tumor microenvironment. Adipose tissue-derived mesenchymal stromal cells (ASCs) are recruited to breast cancer by many mechanisms, including hypoxia, and contribute to metastatic transition of the cancer. Breast cancers are characterized by regions of hypoxia, which can be temporally unstable owing to a mismatch between oxygen supply and consumption. Using a high-sensitivity nanopatterned stromal invasion assay, we found that ASCs could promote stromal invasion of not only breast cancer cell lines but also MCF10A1, a cell line derived from untransformed breast epithelium. RNA sequencing of MCF10A1 cells conditioned with medium from ASCs revealed upregulation of genes associated with increased cell migration, chemotaxis, and metastasis. Furthermore, we found that fluctuating or oscillating hypoxia could induce senescence in ASCs, which could result in an increased invasive potential in the treated MCF10A1 cells. These findings highlight the complex interplay within the breast cancer microenvironment, hypoxia, and the role of ASCs in transforming even non-cancerous breast epithelium toward an invasive phenotype, providing insights into early metastatic events.
PubMed: 38473331
DOI: 10.3390/cancers16050969 -
Heliyon Mar 2024Recently, heterocyclic compounds such as pyrido [2,3-] pyrimidinones, 1,2,4-triazolopyrimidines, pyrimidoquinazolines, and quinoline derivatives have gained attention...
Recently, heterocyclic compounds such as pyrido [2,3-] pyrimidinones, 1,2,4-triazolopyrimidines, pyrimidoquinazolines, and quinoline derivatives have gained attention from researchers due to their pharmacological and biological activities. To synthesize new compounds, quinoline-2-thioxopyrido [2,3-] pyrimidinone and methylthioquinoline-pyrido [2,3-] pyrimidinones were used as starting materials. The new compounds synthesized were quinoline-pyrido [2,3-] (DeGoey et al., 2013; Gouda et al., 2020; Dangolani et al., 2018) [1, 2,4]triazolopyrimidinones , 2-methylsulfonyl-quinoline-pyrido [2,3-]pyrimidinone , pyrido [2,3-]pyrimidine derivatives, pyridopyrimido (Gouda et al., 2020; DeGoey et al., 2013) 2,12,1-b] quinazoline , pyrido [(Khajouei et al., 2021; Gouda et al., 2020) 3,23,2-e]bis (1,2,4-triazole)pyrimidine and pyridopyrimido-diquinazoline-dione derivatives. These compounds were synthesized with high efficiency, producing yields ranging from 69% to 90%, under moderate conditions, through treating or with various reagents such as anthranilic acid, phosphorus oxychloride, hydrazine hydrate, formic acid, glacial acetic acid, arylamine (aniline, 4-chloroaniline, or 4-methoxyaniline), and sec-amine (piperazine or morpholine). The new structures of the synthesized compounds were verified using various spectroscopic procedures, such as IR, NMR, and mass spectra. Molecular docking studies were carried out to investigate and discuss how the prepared compounds bind to amino acids such as Estrogen Receptor alpha, EGFR, and NADPH oxidase protein. Also, the synthesized products were tested for their anticancer and antioxidant activities against the (MCF-7) breast carcinoma cell line and human normal Retina pigmented epithelium cells (RPE-1). The study on the structure-activity relationship (SAR) established a correlation between the chemical structure of the newly synthesized compounds and their anticancer activity. The findings suggest that compounds , ,, and exhibited promising anticancer activity and antioxidant effects as measured by DPPH inhibition.
PubMed: 38468950
DOI: 10.1016/j.heliyon.2024.e26735 -
Current Molecular Medicine Mar 2024Inflammatory bowel disease (IBD), a chronic inflammatory condition of the human intestine, comprises Crohn's Disease (CD) and Ulcerative Colitis (UC). IBD causes severe...
Inflammatory bowel disease (IBD), a chronic inflammatory condition of the human intestine, comprises Crohn's Disease (CD) and Ulcerative Colitis (UC). IBD causes severe gastrointestinal symptoms and increases the risk of developing colorectal carcinoma. Although the etiology of IBD remains ambiguous, complex interactions between genetic predisposition, microbiota, epithelial barrier, and immune factors have been implicated. The disruption of intestinal homeostasis is a cardinal characteristic of IBD. Patients with IBD exhibit intestinal microbiota dysbiosis, impaired epithelial tight junctions, and immune dysregulation; however, the relationship between them is not completely understood. As the largest body surface is exposed to the external environment, the gastrointestinal tract epithelium is continuously subjected to environmental and endogenous stressors that can disrupt cellular homeostasis and survival. Heat shock proteins (HSPs) are endogenous factors that play crucial roles in various physiological processes, such as maintaining intestinal homeostasis and influencing IBD progression. Specifically, HSPs share an intricate association with microbes, intestinal epithelium, and the immune system. In this review, we aim to elucidate the impact of HSPs on IBD development by examining their involvement in the interactions between the intestinal microbiota, epithelial barrier, and immune system. The recent clinical and animal models and cellular research delineating the relationship between HSPs and IBD are summarized. Additionally, new perspectives on IBD treatment approaches have been proposed.
PubMed: 38465431
DOI: 10.2174/0115665240286793240306053111 -
Scientific Reports Mar 2024Detecting breast tissue alterations is essential for cancer diagnosis. However, inherent bidimensionality limits histological procedures' effectiveness in identifying...
Detecting breast tissue alterations is essential for cancer diagnosis. However, inherent bidimensionality limits histological procedures' effectiveness in identifying these changes. Our study applies a 3D virtual histology method based on X-ray phase-contrast microtomography (PhC CT), performed at a synchrotron facility, to investigate breast tissue samples including different types of lesions, namely intraductal papilloma, micropapillary intracystic carcinoma, and invasive lobular carcinoma. One-to-one comparisons of X-ray and histological images explore the clinical potential of 3D X-ray virtual histology. Results show that PhC CT technique provides high spatial resolution and soft tissue sensitivity, while being non-destructive, not requiring a dedicated sample processing and being compatible with conventional histology. PhC CT can enhance the visualization of morphological characteristics such as stromal tissue, fibrovascular core, terminal duct lobular unit, stromal/epithelium interface, basement membrane, and adipocytes. Despite not reaching the (sub) cellular level, the three-dimensionality of PhC CT images allows to depict in-depth alterations of the breast tissues, potentially revealing pathologically relevant details missed by a single histological section. Compared to serial sectioning, PhC CT allows the virtual investigation of the sample volume along any orientation, possibly guiding the pathologist in the choice of the most suitable cutting plane. Overall, PhC CT virtual histology holds great promise as a tool adding to conventional histology for improving efficiency, accessibility, and diagnostic accuracy of pathological evaluation.
Topics: Humans; Female; X-Rays; Breast Neoplasms; X-Ray Microtomography; Microscopy, Phase-Contrast; Histological Techniques; Imaging, Three-Dimensional
PubMed: 38461221
DOI: 10.1038/s41598-024-56341-6